scholarly journals Serotonin and beyond—a tribute to Manfred Göthert (1939-2019)

2021 ◽  
Author(s):  
H. Bönisch ◽  
K. B. Fink ◽  
B. Malinowska ◽  
G. J. Molderings ◽  
E. Schlicker
Keyword(s):  
Molecular Study ◽  
Inhibitory Effect ◽  
Presynaptic Receptors ◽  
Cellular Level ◽  
Receptor Subtypes ◽  
Clinical Effects ◽  
Allosteric Effect ◽  
Human Brain Tissue ◽  
Subsequent Decrease ◽  
Voltage Dependent

AbstractManfred Göthert, who had served Naunyn-Schmiedeberg’s Arch Pharmacol as Managing Editor from 1998 to 2005, deceased in June 2019. His scientific oeuvre encompasses more than 20 types of presynaptic receptors, mostly on serotoninergic and noradrenergic neurones. He was the first to identify presynaptic receptors for somatostatin and ACTH and described many presynaptic receptors, known from animal preparations, also in human tissue. In particular, he elucidated the pharmacology of presynaptic 5-HT receptors. A second field of interest included ligand-gated and voltage-dependent channels. The negative allosteric effect of anesthetics at peripheral nACh receptors is relevant for the peripheral clinical effects of these drugs and modified the Meyer-Overton hypothesis. The negative allosteric effect of ethanol at NMDA receptors in human brain tissue occurred at concentrations found in the range of clinical ethanol intoxication. Moreover, the inhibitory effect of gabapentinoids on P/Q Ca2+ channels and the subsequent decrease in AMPA-induced noradrenaline release may contribute to their clinical effect. Another ligand-gated ion channel, the 5-HT3 receptor, attracted the interest of Manfred Göthert from the whole animal via isolated preparations down to the cellular level. He contributed to that molecular study in which 5-HT3 receptor subtypes were disclosed. Finally, he found altered pharmacological properties of 5-HT receptor variants like the Arg219Leu 5-HT1A receptor (which was also shown to be associated with major depression) and the Phe124Cys 5-HT1B receptor (which may be related to sumatriptan-induced vasospasm). Manfred Göthert was a brilliant scientist and his papers have a major impact on today’s pharmacology.

scholarly journals Role of beta-adrenergic receptor subtypes in pig uterus contractility with inflammation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Barbara Jana ◽  
Jarosław Całka
Keyword(s):  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Domestic Animals ◽  
Inhibitory Effect ◽  
Receptor Subtypes ◽  
Beta Adrenergic Receptor ◽  
Pharmacological Modulation ◽  
Uterine Inflammation ◽  
Myometrial Contractility

AbstractUterine inflammation is a very common and serious condition in domestic animals. To development and progression of this pathology often lead disturbances in myometrial contractility. Participation of β1-, β2- and β3-adrenergic receptors (ARs) in noradrenaline (NA)-influenced contractility of the pig inflamed uterus was studied. The gilts of SAL- and E.coli-treated groups were administered saline or E.coli suspension into the uterine horns, respectively. Laparotomy was only done in the CON group. Compared to the period before NA administration, this neurotransmitter reduced the tension, amplitude and frequency in uterine strips of the CON and SAL groups. In the E.coli group, NA decreased the amplitude and frequency, and these parameters were lower than in other groups. In the CON, SAL and E.coli groups, β1- and β3-ARs antagonists in more cases did not significantly change and partly eliminated NA inhibitory effect on amplitude and frequency, as compared to NA action alone. In turn, β2-ARs antagonist completely abolished NA relaxatory effect on these parameters in three groups. Summarizing, NA decreases the contractile amplitude and frequency of pig inflamed uterus via all β-ARs subtypes, however, β2-ARs have the greatest importance. Given this, pharmacological modulation of particular β-ARs subtypes can be used to increase inflamed uterus contractility.

scholarly journals Modulation of High-Voltage Activated Ca2+ Channels in the Rat Periaqueductal Gray Neurons by μ-Type Opioid Agonist

1997 ◽  
Vol 77 (3) ◽  
pp. 1418-1424 ◽  
Author(s):  
Chang-Ju Kim ◽  
Jeong-Seop Rhee ◽  
Norio Akaike
Keyword(s):  
G Proteins ◽  
Opioid Receptor ◽  
High Voltage ◽  
Inhibitory Effect ◽  
Periaqueductal Gray ◽  
Dependent Manner ◽  
Opioid Agonist ◽  
Voltage Clamp Condition ◽  
Voltage Dependent ◽  
Clamp Condition

Kim, Chang-Ju, Jeong-Seop Rhee, and Norio Akaike. Modulation of high-voltage activated Ca2+ channels in the rat periaqueductal gray neurons by μ-type opioid agonist. J. Neurophysiol. 77: 1418–1424, 1997. The effect of μ-type opioid receptor agonist, D-Ala2,N-MePhe4,Gly5-ol-enkephalin (DAMGO), on high-voltage-activated (HVA) Ca2+ channels in the dissociated rat periaqueductal gray (PAG) neurons was investigated by the use of nystatin-perforated patch recording mode under voltage-clamp condition. Among 118 PAG neurons tested, the HVA Ca2+ channels of 38 neurons (32%) were inhibited by DAMGO (DAMGO-sensitive cells), and the other 80 neurons (68%) were not affected by DAMGO (DAMGO-insensitive cells). The N-, P-, L-, Q-, and R-type Ca2+ channel components in DAMGO-insensitive cells shared 26.9, 37.1, 22.3, 7.9, and 5.8%, respectively, of the total Ca2+ channel current. The channel components of DAMGO-sensitive cells were 45.6, 25.7, 21.7, 4.6, and 2.4%, respectively. The HVA Ca2+ current of DAMGO-sensitive neurons was inhibited by DAMGO in a concentration-, time-, and voltage-dependent manner. Application of ω-conotoxin-GVIA occluded the inhibitory effect of DAMGO ∼70%. So, HVA Ca2+ channels inhibited by DAMGO were mainly the N-type Ca2+ channels. The inhibitory effect of DAMGO on HVA Ca2+ channels was prevented almost completely by the pretreatment of pertussis toxin (PTX) for 8–10 h, suggesting that DAMGO modulation on N-type Ca2+ channels in rat PAG neurons is mediated by PTX-sensitive G proteins. These results indicate that μ-type opioid receptor modulates N-type HVA Ca2+ channels via PTX-sensitive G proteins in PAG neurons of rats.

Biochemical and Clinical Effects of Ethane-1-Hydroxy-1,1-Diphosphonate in Calcium Nephrolithiasis

1978 ◽  
Vol 54 (5) ◽  
pp. 509-516 ◽  
Author(s):  
J. M. Baumann ◽  
S. Bisza ◽  
H. Fleisch ◽  
M. Wacker
Keyword(s):  
Urinary Excretion ◽  
Average Rate ◽  
Stone Formation ◽  
Placebo Treatment ◽  
Inhibitory Effect ◽  
Urinary Concentration ◽  
Clinical Effects ◽  
Inorganic Pyrophosphate ◽  
Urinary Tract Stones ◽  
Calcium Crystals

1. The short- and longer-term effects of ethane-1-hydroxy-1,1-diphosphonate (EHDP), an inhibitor of crystal growth and potential preventive agent against urinary tract stones in man, have been studied. 2. Measurement of urinary excretion of EHDP was used to define the best dosage regimen. When 4·4 mmol of EHDP was given daily in four divided doses the urinary concentration of EHDP achieved was high enough (10−5 mol/l) to inhibit the crystallization of calcium crystals throughout the day. 3. Nine patients with recurrent calcium stones were given this dose of EHDP daily for 12 months and seven were then studied for a further 12 months under placebo. During treatment with EHDP, inhibitory activity in urine towards precipitation of calcium phosphate was restored from low values to greatly above normal. This could be accounted for by the inhibitory effect of EHDP itself, coupled with an increase in urinary inorganic pyrophosphate. After stopping EHDP the excretion of EHDP rapidly fell to undetectable levels but the excretion of pyrophosphate remained elevated throughout the 12 months of placebo treatment. EHDP also induced a rise in plasma phosphate and an increase in the urinary excretion of oxalic acid and uric acid, but these changes were all fully reversible when EHDP was stopped. 4. The average rate of stone formation per patient per year decreased from 2·4 to 0·2 during treatment with EHDP and remained low during the following 24 months. However, the dose needed for this effect is known to affect bone turnover and mineralization.

scholarly journals Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes

2019 ◽  
Author(s):  
Muhmmad Omar-Hmeadi ◽  
Per-Eric Lund ◽  
Nikhil R Gandasi ◽  
Anders Tengholm ◽  
Sebastian Barg
Keyword(s):  
Type 2 Diabetes ◽  
Glucagon Secretion ◽  
Cellular Level ◽  
Membrane Excitability ◽  
Granule Exocytosis ◽  
Paracrine Effects ◽  
Voltage Dependent ◽  
Resolution Imaging ◽  
Glucose Sensitivity

AbstractGlucagon is secreted from pancreatic α-cells to activate gluconeogenesis and other pathways that raise blood glucose during hypoglycemia. Glucose-dependent regulation of glucagon secretion involves both α-cell-intrinsic mechanisms and paracrine control through insulin and somatostatin. In type-2 diabetes (T2D) inadequately high glucagon levels contribute to hyperglycemia. To understand these disease-associated changes at the cellular level, and to isolate intrinsic and paracrine effects, we analyzed glucagon granule exocytosis and membrane excitability in isolated α-cells from 56 non-diabetic (ND) and 15 T2D human donors. High resolution imaging showed that glucagon granule exocytosis had a U-shaped sensitivity to glucose, with the slowest rate around 7 mM glucose, and accelerated rates at <5 and >10 mM glucose. Exocytosis was reduced in T2D α-cells, but their glucose sensitivity remained intact and there were no changes in voltage-dependent ion currents or granule trafficking. Instead, α-cells from T2D donors were markedly insensitive to somatostatin and insulin, which rapidly inhibited exocytosis and electrical activity in ND cells. Thus, intrinsic mechanisms do not inhibit glucagon secretion at hyperglycemia, and elevated glucagon levels in human T2D reflect an insensitivity of α-cells to paracrine inhibition.

scholarly journals α-Crystallin B prevents apoptosis after H2O2 exposure in mouse neonatal cardiomyocytes

2012 ◽  
Vol 303 (8) ◽  
pp. H967-H978 ◽  
Author(s):  
Roxana Chis ◽  
Parveen Sharma ◽  
Nicolas Bousette ◽  
Tetsuaki Miyake ◽  
Aaron Wilson ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Cardiac Tissue ◽  
Small Heat Shock Protein ◽  
Subcellular Fractionation ◽  
Cellular Level ◽  
Protective Mechanism ◽  
Protective Effects ◽  
Neonatal Cardiomyocytes ◽  
Caspase 12 ◽  
Voltage Dependent

α-Crystallin B (cryAB) is the most abundant small heat shock protein in cardiomyocytes (CMs) and has been shown to have potent antiapoptotic properties. Because the mechanism by which cryAB prevents apoptosis has not been fully characterized, we examined its protective effects at the cellular level by silencing cryAB in mouse neonatal CMs using lentivector-mediated transduction of short hairpin RNAs. Subcellular fractionation of whole hearts showed that cryAB is cytosolic under control conditions, and after H2O2 exposure, it translocates to the mitochondria. Phosphorylated cryAB (PcryAB) is mainly associated with the mitochondria, and any residual cytosolic PcryAB translocates to the mitochondria after H2O2 exposure. H2O2 exposure caused increases in cryAB and PcryAB levels, and cryAB silencing resulted in increased levels of apoptosis after exposure to H2O2. Coimmunoprecipitation assays revealed an apparent interaction of both cryAB and PcryAB with mitochondrial voltage-dependent anion channels (VDAC), translocase of outer mitochondrial membranes 20 kDa (TOM 20), caspase 3, and caspase 12 in mouse cardiac tissue. Our results are consistent with the conclusion that the cardioprotective effects of cryAB are mediated by its translocation from the cytosol to the mitochondria under conditions of oxidative stress and that cryAB interactions with VDAC, TOM 20, caspase 3, and caspase 12 may be part of its protective mechanism.

scholarly journals Cigarette Smoke Extract Inhibits Platelet Aggregation by Suppressing Cyclooxygenase Activity

TH Open ◽  
2017 ◽  
Vol 01 (02) ◽  
pp. e122-e129
Author(s):  
Hitoshi Kashiwagi ◽  
Koh-ichi Yuhki ◽  
Yoshitaka Imamichi ◽  
Fumiaki Kojima ◽  
Shima Kumei ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Cigarette Smoke ◽  
Platelet Function ◽  
Inhibitory Effect ◽  
Cigarette Smoke Extract ◽  
Human Platelets ◽  
Receptor Subtypes ◽  
Ic50 Value ◽  
Induced Aggregation ◽  
Cox 1

AbstractThe results of studies that were performed to determine whether cigarette smoking affects platelet function have been controversial, and the effects of nicotine- and tar-free cigarette smoke extract (CSE) on platelet function remain to be determined. The aim of this study was to determine the effect of CSE on platelet aggregation and to clarify the mechanism by which CSE affects platelet function. CSE inhibited murine platelet aggregation induced by 9,11-dideoxy-9α,11α-methanoepoxy-prosta-5Z,13E-dien-1-oic acid (U-46619), a thromboxane (TX) A2 receptor agonist, and that induced by collagen with respective IC50 values of 1.05 ± 0.14% and 1.34 ± 0.19%. A similar inhibitory action of CSE was also observed in human platelets. CSE inhibited arachidonic acid–induced TXA2 production in murine platelets with an IC50 value of 7.32 ± 2.00%. Accordingly, the inhibitory effect of CSE on collagen-induced aggregation was significantly blunted in platelets lacking the TXA2 receptor compared with the inhibitory effect in control platelets. In contrast, the antiplatelet effects of CSE in platelets lacking each inhibitory prostanoid receptor, prostaglandin (PG) I2 receptor and PGE2 receptor subtypes EP2 and EP4, were not significantly different from the effects in respective control platelets. Among the enzymes responsible for TXA2 production in platelets, the activity of cyclooxygenase (COX)-1 was inhibited by CSE with an IC50 value of 1.07 ± 0.15% in an uncompetitive manner. In contrast, the activity of TX synthase was enhanced by CSE. The results indicate that CSE inhibits COX-1 activity and thereby decreases TXA2 production in platelets, leading to inhibition of platelet aggregation.

Ca2+-dependent desensitization of insulin secretion by strong potassium depolarization

2012 ◽  
Vol 303 (2) ◽  
pp. E223-E233 ◽  
Author(s):  
M. Willenborg ◽  
M. Belz ◽  
K. Schumacher ◽  
A. Paufler ◽  
K. Hatlapatka ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Concentration ◽  
Choline Chloride ◽  
Inhibitory Effect ◽  
High K ◽  
Nacl Concentration ◽  
Voltage Dependent ◽  
Fast Decline ◽  
Insulinotropic Effect ◽  
Initial Peak

Depolarization by a high K+ concentration is a widely used experimental tool to stimulate insulin secretion. The effects occurring after the initial rise in secretion were investigated here. After the initial peak a fast decline occurred, which was followed by a slowly progressive decrease in secretion when a strong K+ depolarization was used. At 40 mM KCl, but not at lower concentrations, the decrease continued when the glucose concentration was raised from 5 to 10 mM, suggesting an inhibitory effect of the K+ depolarization. When tolbutamide was added instead of the glucose concentration being raised, a complete inhibition down to prestimulatory values was observed. Equimolar reduction of the NaCl concentration to preserve isoosmolarity enabled an increase in secretion in response to glucose. Unexpectedly, the same was true when the Na+-reduced media were made hyperosmolar by choline chloride or mannitol. The insulinotropic effect of tolbutamide was not rescued by the compensatory reduction of NaCl, suggesting a requirement for activated energy metabolism. These inhibitory effects could not be explained by a lack of depolarizing strength or by a diminished free cytosolic Ca2+ concentration ([Ca2+]i). Rather, the complexation of extracellular Ca2+ concomitant with the K+ depolarization markedly diminished [Ca2+]i and attenuated the inhibitory action of 40 mM KCl. This suggests that a strong but not a moderate depolarization by K+ induces a [Ca2+]i-dependent, slowly progressive desensitization of the secretory machinery. In contrast, the decline immediately following the initial peak of secretion may result from the inactivation of voltage-dependent Ca2+ channels.

scholarly journals Inhibitory Effect of Metalloproteinase Inhibitors on Skin Cell Inflammation Induced by Jellyfish Nemopilema nomurai Nematocyst Venom

Toxins ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 156 ◽  
Author(s):  
Aoyu Li ◽  
Huahua Yu ◽  
Rongfeng Li ◽  
Song Liu ◽  
Ronge Xing ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Research Area ◽  
Cellular Level ◽  
Inflammatory Factors ◽  
Nemopilema Nomurai ◽  
Whole Process ◽  
Skin Cell ◽  
Tnf Α ◽  
Main Components ◽  
Jellyfish Venom

Jellyfish envenomations result in extensive dermatological symptoms, clinically named as jellyfish dermatitis, which can seriously affect the daily activities and physical health of people. Inflammatory response accompanies the whole process of jellyfish dermatitis and the complexity of jellyfish venom components makes it difficult to treat jellyfish dermatitis symptoms effectively. Moreover, inhibiting inflammation is essential for the treatment of jellyfish stings and exploring the main components of jellyfish venom that cause inflammation is an urgent research area. In this study, the inhibitory effects of matrix metalloproteinase (MMP) inhibitors for venom-induced inflammation were explored at a cellular level. The expression of the three inflammatory factors, IL-6, TNF-α and MCP-1 in two skin cell lines, human keratinocyte cells (HaCaT) and human embryonic skin fibroblasts cells (CCC-ESF-1), at the cellular level, after treatment with the inhibitors of jellyfish Nemopilema nomurai (N. nomurai) nematocyst venom (NnNV-I), were determined. The results showed that inhibitors of MMP can significantly reduce the toxic effects of jellyfish Nemopilema nomurai nematocyst venom (NnNV) to skin cells. The expression levels of the three inflammatory factors IL-6, MCP-1, and TNF-α in the cells were also significantly decreased, indicating that MMPs in jellyfish venom are probably vital factors leading to jellyfish dermatitis. This study is beneficial in the prevention and treatment of jellyfish stings.

Stimulation of neurons in rat ARC inhibits gastric acid secretion via hypothalamic CRF1/2- and NPY-Y1 receptors

2003 ◽  
Vol 285 (6) ◽  
pp. G1075-G1083 ◽  
Author(s):  
Johannes J. Tebbe ◽  
Silke Mronga ◽  
Martin K.-H. Schäfer ◽  
Jens Rüter ◽  
Peter Kobelt ◽  
...  
Keyword(s):  
Acid Secretion ◽  
Receptor Antagonist ◽  
Gastric Acid Secretion ◽  
Gastric Acid ◽  
Excitatory Amino Acid ◽  
Inhibitory Effect ◽  
Receptor Subtypes ◽  
Npy Receptor ◽  
Y1 Receptors ◽  
Open Question

Neuropeptide Y (NPY) neuronal projections from the arcuate nucleus (ARC) have been proposed to target corticotropin-releasing factor (CRF)-positive neurons in the paraventricular nucleus (PVN) as part of the ARC-PVN axis. The existence of a positive feedback loop involving CRF receptors in the PVN has been suggested. Exogenous NPY and CRF in the PVN have been shown to inhibit gastric acid secretion. Recently, we have demonstrated that activation of ARC neurons inhibits gastric acid secretion via vagal pathways. To what extent NPY- and CRF-mediated mechanisms in the PVN contribute to the CNS modulation of gastric acid secretion is still an open question. In the present study, we performed consecutive bilateral microinjections of antagonists to NPY receptor subtypes Y1 and Y2 and to CRF1/2 receptors in the PVN and of the excitatory amino acid kainate in the ARC to assess the role of NPY- and CRF-mediated mechanisms in the kainate-induced effects on gastric acid secretion. Gastric acid secretion was measured at the basal condition and during pentagastrin (16 μg/kg body wt) stimulation. Microinjection of vehicle in the PVN and kainate in the ARC decreased gastric acid secretion. Microinjection of the specific NPY-Y1 receptor antagonist BIBP-3226 (200 pmol) and the nonspecific CRF1/2 antagonist astressin (30 pmol) in the PVN abolished the inhibitory effect of neuronal activation in the ARC by kainate on gastric acid secretion. The CRF antagonist astressin was more effective. Pretreatment with the NPY-Y2 receptor antagonist BIIE-0246 (120 pmol) in the PVN had no significant effect. Our results indicate that activation of neurons in the ARC inhibits gastric acid secretion via CRF1/2 and NPY-Y1 receptor-mediated pathways in the PVN.

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